Common depth and sample position noninvasive glucose concentration determination analyzer apparatus and method of use thereof

ABSTRACT

The invention comprises a method and apparatus for sampling optical pathways having a common tissue depth, such as a maximum mean depth of penetration in the dermis, with a common sample position of a person for analysis in a noninvasive analyte property determination system, comprising the steps of: probing skin with a range of illumination zone-to-detection zone distances with at least two wavelength ranges and detecting, using a set of detectors, illumination zone-to-detection zone distances having mean optical pathways probing the common tissue layer, such as without the mean optical pathways entering the subcutaneous fat layer of the person. Optionally, the skin tissue layers are modulated and/or treated via tissue displacement before and/or during data collection. Optionally, given illumination zone-to-detection zone distances are dynamically selected based upon a measure of state of the skin of the person.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is:

-   -   a continuation-in-part of U.S. patent application Ser. No.        16/691,611 filed Nov. 22, 2019;    -   a continuation-in-part of U.S. patent application Ser. No.        16/691,615 filed Nov. 22, 2019; and    -   a continuation-in-part of U.S. patent application Ser. No.        15/829,877 filed Dec. 2, 2017, which is a continuation-in-part        of U.S. patent application Ser. No. 15/636,073 filed Jun. 28,        2017, which claims benefit of U.S. provisional patent        application No. 62/355,507 filed Jun. 28, 2016.

BACKGROUND OF THE INVENTION Field of the Invention

The invention relates generally to noninvasively determining glucoseconcentration in a living body using an optical analyzer, such as avisible/near-infrared noninvasive glucose concentration determinationanalyzer.

Discussion of the Prior Art

There exists in the art a need for noninvasively determining glucoseconcentration in the human body.

SUMMARY OF THE INVENTION

The invention comprises a noninvasive glucose concentration analyzerapparatus and method of use thereof.

DESCRIPTION OF THE FIGURES

A more complete understanding of the present invention is derived byreferring to the detailed description and claims when considered inconnection with the Figures, wherein like reference numbers refer tosimilar items throughout the Figures.

FIG. 1 illustrates use of an applied force-optic analyzer;

FIG. 2 illustrates a noninvasive analyzer;

FIG. 3A illustrates an applied force system, FIG. 3B illustrates atransducer, FIG. 3C illustrates transducer movement normal to an opticalaxis, FIG. 3D illustrates a z-axis transducer, and FIG. 3E illustrates amulti-axes off-center spinning mass transducer;

FIG. 4A illustrates spectrometer components, FIG. 4B illustrates anaffixing layer, and FIG. 4C illustrates a coupling fluid enhancedaffixer;

FIG. 5A illustrates a force system coupled to a spectrometer and FIG. 5Billustrates a force system embedded in a spectrometer;

FIG. 6 illustrates photons interacting with applied force wave(s) intissue;

FIG. 7A illustrates absorbance of skin constituents, FIG. 7B illustratesfat and protein absorbance, FIG. 7C illustrates intensity as a functionof depth/distance, and FIG. 7D illustrates scattering;

FIG. 8 illustrates detector selection;

FIG. 9 illustrates changing detector selection with tissue change;

FIG. 10A illustrates a transducer force applicator and FIG. 10B and FIG.10C illustrate transducer force detectors in lines and arcsrespectively;

FIG. 11A illustrates radial optical detection of force waves, FIG. 11Billustrates an array of optical detectors, and FIG. 11C illustrates arcsof optical detectors;

FIG. 12 illustrates optical probes observing tissue modified by forcewaves in a noninvasive glucose concentration determinationsystem/analyzer;

FIG. 13 illustrates a multi-sensor analyzer system;

FIG. 14A illustrates spirally distributed detectors and FIG. 14B andFIG. 14C illustrate depth and radial distance resolution;

FIG. 15A, FIG. 15B, FIG. 15C, and FIG. 15D illustrate depth selectionfrom various angles in two separate units;

FIG. 16A, FIG. 16B, FIG. 16C, and FIG. 16D illustrate tissue sampleposition selection; and

FIG. 17 illustrates a common depth and common detector analyzer probetip; and

FIG. 18 illustrates a common depth and common sample position probe tip.

Elements and steps in the figures are illustrated for simplicity andclarity and have not necessarily been rendered according to anyparticular sequence. For example, steps that are performed concurrentlyor in different order are illustrated in the figures to help improveunderstanding of embodiments of the present invention.

PROBLEM

There remains in the art a need for a noninvasive glucose concentrationanalyzer.

DETAILED DESCRIPTION OF THE INVENTION

The invention comprises a method and apparatus for sampling opticalpathways having a common tissue depth, such as a maximum mean depth ofpenetration in the dermis, with a common sample position of a person foranalysis in a noninvasive analyte property determination system,comprising the steps of: probing skin with a range of illuminationzone-to-detection zone distances with at least two wavelength ranges,which optionally overlap, and detecting, using a set of detectors,illumination zone-to-detection zone distances having mean opticalpathways probing the common tissue layer, such as without the meanoptical pathways entering the subcutaneous fat layer of the person.Optionally, the skin tissue layers are modulated and/or treated viatissue displacement before and/or during data collection. Optionally,given illumination zone-to-detection zone distances are dynamicallyselected based upon a measure of state of the skin of the person.

Herein, generally, when describing an optical portion of the appliedforce-optic analyzer, a z-axis is aligned with a mean direction of thephotons in a given sub-portion of the analyzer, such as along alongitudinal path of the photons into skin of a subject, and x- andy-axes form a plane perpendicular to the z-axis, such as at an interfacepoint of incident photons into the skin of the subject. At the point ofcontact of the applied force-optic analyzer with the biological sample,the z-axis is normal/perpendicular to the sample and the x/y-planetangentially contacts the sample. For instance, the light movesdominantly along the z-axis along vectors approaching perpendicular toan upper arm of a subject or a patient and the x/y-plane tangentiallytouches the upper arm along the z-axis. In particular cases, a secondx,y,z-axis system is used to describe the sample itself, such as az-axis being along the longitudinal length of a body part, such as alonga digit or a finger or along the length of an arm section and thex/y-plane in this case is a cross-section plane of the body part.

A sample is optionally any material responding to an applied physicalforce in a manner observed by a probing optical system. However, forclarity of presentation and without loss of generality, the sample isdescribed as a person, subject, patient, and/or a living tissue, such asskin and/or a portion of a human or animal. While the analyzer isdescribed as a noninvasive analyzer probing into and optionally throughthe outer layers of skin, the noninvasive analyzer is optionally used asand or in conjunction with a minimally invasive glucose concentrationanalyzer and/or in conjunction with an invasive glucose concentrationanalyzer.

Herein, an illumination zone and/or an imaging zone is a point, region,or area of intersection of the illumination/imaging beam and/or pulsewith an incident surface of the sample to yield a spectrum and/or animage of a desired volume of the sample. Herein, a detection zone is apoint, region, or area of the sample sampled and/or visualized by one ormore detectors. Similarly, herein an applied force zone is an incidentpoint, region, or area of intersection at which an applied force isapplied to the sample and a detected force zone is a point, region, orarea of the sample interfacing with a force detector.

Applied Force-Optic Analyzer

Referring now to FIG. 1, a noninvasive analysis system 100 using ananalyzer 110, such as an applied force-optic analyzer system isillustrated. Generally, an optional force system 200 is used to applyone or more applied forces, physical distortions, and/or force waves toa sample 300. The applied force travels with a wave front, as a wave, ina pattern of compression and rarefication, and/or as a travelingdisplacement through the sample 300 or portions thereof. With or withoutapplication of the force waves, a spectrometer 140 is used tononinvasively collect spectra of the sample 300 and photometricallydetermine one or more properties of the sample, such as a glucoseconcentration. As described infra, the applied force is optionally inthe form of an acoustic wave. However, the applied force is optionallyand preferably a physical displacement of a portion of skin of a person,where the physical displacement is caused by movement of a mechanicalobject relative to the body to yield a time varying displacement of skinand/or constituents of the skin by the mechanical object. As described,infra, a variety of force provider technologies are available tovariably displace the skin in a controlled manner. For clarity ofpresentation and without loss of generality, a transducer is used as anexample to represent an applied force section of the force system 200,where a transducer comprises a device that receives a signal/force inthe form of one type of energy and converts it to a signal/force inanother form. Again for clarity of presentation and without loss ofgenerality, a piezoelectric actuator is used to represent a transducerand an off-center spinning mass is used to represent a transducer.Hence, again for clarity of presentation and without loss of generality,a piezoelectric-optical analyzer or simply a piezo-optic analyzer, atransducer, and/or a transducer force applicator is used to describe anyand all applied force electromechanical sources in the force system 200.Optionally, more than one transducer is used to yield displacement ofthe surface of the skin/skin, such as at a function of time and/orposition.

Referring now to FIG. 2, use of the analyzer 110 is described.Generally, the analyzer 110 is optionally calibrated using a reference310 and is used to measure a subject 320, where the subject 320 is anexample of the sample 300. Optionally and preferably, the analyzer 110and/or a constituent thereof communicates with a remote system 130 usinga wireless communication protocol 112 and/or a wired communicationprotocol.

Force System

Referring now to FIGS. 3(A-E), the force system 200 is furtherdescribed. Generally, the force system 200 comprises a force deliverytransducer that directly and/or indirectly contacts the sample 300, suchas an outer skin surface 330 of the subject 320 and/or a patient. Thesubject 320 has many skin layers 340, which are also referred to hereinas tissue layers. For clarity of presentation, the skin layers 340 arerepresented as having a first skin layer, such as a stratum corneum 342;a second skin layer, such as an epidermis 344 or epidermal layer; athird skin layer, such as a dermis 346 or dermis layer; and a fourthlayer, such as subcutaneous fat 348 or a subcutaneous fat layer. It isrecognized that skin is a complex organ with many additional layers andmany sub-layers of the named layers that vary in thickness and shapewith time. However, for clarity of presentation and without loss ofgenerality, the stratum corneum, epidermis, dermis, and subcutaneous fatlayers are used to illustrate impact of the force delivery transducer onthe skin layers 340 of the subject 320 and how the applied force wavesalter optical paths of probing photons in the spectrometer 140 of theanalyzer 110 in the noninvasive analysis system 100.

Still referring to FIG. 3A, at a first time, t₁, the tissue layers 340are in a first state. As illustrated, the tissue layers 340 are in acompressed state 340, such as a result of mass of the force system 200sitting on the skin surface 330, as a result of dehydration of thesubject 320, and/or as a result of a physiological and/or environmentalforce on the tissue layers 340 of the subject. At a second time, t₂, theforce system 200 applies a force wave 250 to the skin surface 330 of thepatient 320, which sequentially propagates into the stratum corneum 342,epidermis 344, dermis 346, and given enough force into the subcutaneousfat 348. In additional to the force wave propagating into the skinlayers 340 along the z-axis, the force wave propagates radially throughthe skin layers, such as along the x/y-plane of the skin layers. Asillustrated at the second time, t₂, as the force wave 250 propagatesinto the tissue layers 340, the tissue layers expand and/or rarefy, suchthat the thickness of the epidermis 344 and/or the dermis 346 layersexpands. The rarefication of the epidermis 344 and particularly thedermis 346 allows an increased and/or enhanced perfusion of blood 350into the rarefied layers. The increased prefusion increases waterconcentration in the perfused layers, increase and/or changes distancebetween cells in the perfused layers, and/or changes shapes of cells inthe perfused layers, such as through osmolarity induced changes inconcentration in and/or around blood cells, such as red blood cells.Generally, scattering coefficients of the epidermis layer and/orespecially the dermis layer changes, which is observed by thespectrometer 140 in the range of 400 to 2500 nm with larger changes atsmaller wavelengths in the visible, 400 to 700 nm, and/or near-infrared,700 to 2500 nm, regions. As illustrated at the third time, t₃, as theforce wave 250 continues propagation in the tissue layers 340, theperfusion 350 continues to increase, such as to a maximum perfusion. Asillustrated at the fourth time, t₄, after discontinuation of the forcewave 250, the skin layers 340 revert toward the initial state of thenon-force wave induced perfusion to a local minimum perfusion, which maymatch the initial perfusion, is likely higher than the initialperfusion, and is at times less than the initial perfusion due tochanges in state of the environment, such as temperature, and/orgeneralized state of the subject 320, such as hydration, localizedhydration of skin, such as due to food intake, insulin response to foodintake, exercise level, blood pressure, and/or the like. Generally, thetissue layers 340 of the subject increase in thickness and/or rarefyduring application of the transducer applied force wave 250 and decreaseand/or compress after termination of the transducer applied force wave250 to the skin surface 330 of the subject 320. The process of applyingthe force wave 250 is optionally and preferably repeated n times, wheren is a positive integer of greater than 1, 2, 5, 10, 100, 1000, or 5000times in a measurement period of an analyte of the subject 320, such asa glucose concentration. Generally, the cycle of applying the force wave250 results in a compression-rarefication cycle of the tissue thatalters an observed scattering and/or absorbance of probing photons inthe visible and near-infrared regions. The force wave 250 is optionallyand preferably applied as a single ping force in a tissue stateclassification step, as multiple pings in a tissue classification step,and/or as a series of waves during a tissue measurement step. Individualwaves of a set of force waves are optionally controlled and varied interms of one or more of: time of application, amplitude, period,frequency, and/or duty cycle.

Still referring to FIG. 3A and referring now to FIGS. 3(B-D), a forcewave input element 210 of the force system 200 is illustrated. Asillustrated, the force wave input element 210, such as a transducer 220,is equipped with one or of: a left transducer 221, a right transducer222, a front transducer 223, a back transducer 224, a top transducer225, and/or a bottom transducer 226. For instance, the left and/or righttransducers 221, 222 move the force wave input element 210 left and/orright along the x-axis; the front and/or back transducers 223, 224 movethe force wave input element 210 forward and/or back along the y-axis;and/or the top and bottom transducers 225, 226 move the force wave inputelement 210 up and/or down along the z-axis along and/or into the skinsurface 330 of the subject 320, which moves the skin, skin layers 340,and/or skin surface 330 of the subject relative the spectrometer 140and/or is a source of the force wave 250 moving, in the skin layers 340,along the z-axis into the skin, and/or radially outward from aninterface zone of the force wave input element 210 of the force system200. A transducer itself is optionally used as the force wave impulseelement 210. Referring now to FIG. 3E, one or more off-center masselements 230 is optionally spun or rotated, such as with an electricmotor, along one or more of the x,y,z-axes to move the force wave inputelement 210 relative to the skin surface 330 of the subject 320resulting movement of the skin of the subject 320 relative to thespectrometer 140 and/or cycling and/or periodic displacement of thetissue layers 340 of the subject 320 due to movement of the force waveinput element 210 resulting in the force wave(s) 250. Generally, theforce system 200 induces a movement of a sampled zone of skin of thesubject 320, applies a displacement of a sampled zone of the skin of thesubject 320, and/or applies a propagating force wave into and/or througha sample zone of tissue layers 340 of the subject, where the sampledzone is probed using photons from the spectrometer 140 and/or ismeasured using a set of detection zone transducers, described infra. Theforce wave(s) are optionally and preferably applied as a single inputping wave, a set of input ping waves, and/or are applied with afrequency of 0.01 Hz to 60 Hz. Optionally and preferably, the forcewaves 250 are applied with a frequency greater than 0.01, 0.02, 0.05,0.1, or 1 Hz. Optionally and preferably, the force waves 250 are appliedwith a frequency of less than 200, 100, 50, 40, 30, or 20 Hz. Optionallyand preferably, the force waves 250 are applied with a frequency within5, 10, 25, 50, or 100 percent of 2, 4, 6, 8, 10, 12, 15, and 20 Hz.

Optical System

Referring now to FIG. 4A, the spectrometer 140 of the analyzer 110 isfurther described. The spectrometer 140 comprises a source system 400,which provides photons 452 in the visible and/or infrared regions to thesubject 320, such as via a photon transport system 450, at anillumination zone. After scattering and/or absorbance by the tissuelayers 340 of the subject 320, a portion of the photons are detected ata detection zone by a detector system 500. The source system 400includes one or more light sources, such as any of one or more of alight emitting diode, a laser diode, a black body emitter, and/or awhite light source, that emits at any wavelength, range of wavelengths,and/or sets of wavelengths from 400 to 2500 nm. Each source systemphoton source is optionally controlled in terms of time of illumination,intensity, amplitude, wavelength range, and/or bandwidth. The photontransport system 450 comprises any fiber optic, light pipe, airinterface, air transport path, optic, and/or mirror to guide the photonsfrom the light source to one or more illumination zones of the skinsurface 330 of the subject 320 and/or to guide the photons from one ormore detection zones of the skin surface 330 of the subject 320 to oneor more detectors of the detector system 500. Optionally and preferably,the photon transport system 450 includes one or more optical filtersand/or substrates to selectively pass one or more wavelength regions foreach source element of the source system 400 and/or to selectively passone or more wavelength ranges to each detector element of the detectorsystem 500. Herein, the reference 310 is optionally an intensity and/orwavelength reference material used in place of the sample and/or is usedin a optical path simultaneously measured by the analyzer 110.

Still referring to FIG. 4A and referring now to FIG. 4B and FIG. 4C, thesubject 320 optionally and preferably wears the analyzer 110 in thephysical form of a watch head, band, and/or physical element attached tothe body with a band and/or an adhesive. For example, the analyzer 110,the spectrometer 140, the source system 400, and/or the photon transportsystem 450 is optionally attached to the subject 320, such as at thewrist or upper arm, using thin affixing layer 460, such as a doublesided adhesive 462. Referring now to FIG. 4B, the double sided adhesive462 optionally contains an aperture 464 therethrough. The photons 452optionally and preferably pass through the aperture 452 to the skinsurface 330 of the subject. The force wave 250 optionally moves the skinsurface 330 through the aperture into intermittent contact with theanalyzer 110. Optionally, referring now to FIG. 4C, a thin affixinglayer 466, such as less than 1, 0.5, or 0.25 mm thick, is continuous innature in front of the incident surface and/or incident photon couplingzone and/or is continuous in nature in front of the detection zone,where photons exiting the skin surface 330 are detected by the detectorsystem 500. The affixing layer 466 is optionally permeated with a fluid,such as a coupling fluid, an air displacement medium, an opticalcoupling fluid, a fluorocarbon liquid, a fluorocarbon gel, an index ofrefraction matching medium, and/or any fluid that increases a percentageof photons from the source system 400 entering the skin surface 330compared to an absence of the fluid and/or is any fluid that increases apercentage of photons from the tissue layers 340 exiting the detectionzone and reaching the detector system 500 as compared to a case wherethe fluid is not embedded into the affixing layer. Hence, the affixinglayer serves several purposes: attaching the analyzer or a portionthereof to the skin surface 330 of the subject 320, coupling forces fromthe force system 200 to the skin surface 330 of the subject 320, forminga constant sampling interface location on the skin surface 330 of thesubject, and/or altering a coupling efficiency, angular direction,and/or reproducibility of coupling of photons enter the skin of thesubject 320 and/or exiting the skin surface 330.

Coupled Force System/Spectrometer

Referring now to FIG. 5A and FIG. 5B, the force system 200 isillustrated working in conjunction with the spectrometer 140. Referringnow to FIG. 5A, the analyzer 110 is illustrated with the force system200 being attached to and/or within 1, 2, 3, 5, 10, 20, or 50 mm of thespectrometer 140. Referring now to FIG. 5B, the analyzer 110 isillustrated with the force system 200 being integrated into thespectrometer 140, such as within 20, 10, 5, 2, or 1 mm of the sourcesystem 400 of the analyzer 110 and/or in a single housing unit of theanalyzer 110.

Several examples are provided that illustrate how the force system 200alters the tissue layers 340 of the subject 320 and how a selection ofdetected signals from the spectrometer 140 is performed as a function oftime and respective radial separation between the one or moreillumination zones and the one or more detection zones, such as usingwater signal, fat signal, and/or protein signal to determine the correctdetection signals to use for noninvasive glucose concentrationdetermination.

EXAMPLE I

Referring now to FIG. 6, a first example of the analyzer 110 using theforce system 200 and the source system 400 at the same time and/orwithin less than 60, 30, 15, 10, 5, or 1 second of each other isprovided. In this example, the force system 200 applies a force to thetissue layers 340 at a first time, t₁, when the dermis has a first meanz-axis thickness, th₁. Optionally and preferably, the analyzer 110acquires signals representative of the tissue layers 340 of the subject320 using the source system 400 and the detector system 500. Illustratedare three representative photon pathways, p₁₋₃, reaching the detectorsystem 500, such as at a first detector element, a second detectorelement, and a third detector element, respectively, at the first time,t₁, and/or within less than 60, 30, 15, 10, 5, or 2 seconds from thefirst time, t₁. Notably, at the first time, the first photon pathway,p₁, has an average path that does not penetrate into the dermis 346,while the second and third photon pathways, p₂₋₃, have mean pathwaysthat penetrate through the dermis into the subcutaneous fat 348.

In at least one preferred use of the analyzer, noninvasive glucoseconcentration determination is performed using a mean photon pathwaythat penetrates into the dermis 346 and not into the subcutaneous fat348 and/or uses signal from a detector element at a first/minimal radialdistance from the illumination zone, where the first/minimal radialdistance is the smallest radial distance observing an increase in a fatsignal/dominantly fat related signal, such as from the subcutaneous fat348, compared to a water signal/dominantly water related signal fromskin layers 340 closer to the skin surface 332 than that subcutaneousfat 348. Examples of wavelengths containing dominantly water absorbingsignals are wavelengths correlating with the peaks of the waterabsorbance bands 710, FIG. 7A, and/or peaks of the protein absorbancebands, FIG. 7B, and examples of wavelengths containing an increased fatabsorbance to water absorbance ratio when a mean photon path enters thesubcutaneous fat 348 are at the fat absorbance bands 720. For instance,a protein band-to-fat band ratio optionally compares the proteinabsorbance band 730, such as at 1690 nm, with the fat absorbance band720, such as at 1715 nm, where either range is ±5 or ±10 nm. Stillreferring to FIG. 6, at a second time, t₂, the force wave 250 from theforce system 200 has expanded the dermis layer to a second thickness,th₂, which is at least 0.1, 0.2, 0.3, 0.5, 1, 2, 5, 10, 20, or 50%thicker than the first thickness, th₁, and/or has an increased waterabsorbance, as measure by the first, second, and/or third detectorelement of the detector system 500, representative of the first throughthird photon pathway, p₁₋₃, in the condition of the larger dermisthickness at the second time, t₂, as represented by a fourth, fifth, andsixth photon pathway, p₄₋₆. Notably, the fifth and sixth photonpathways, p_(5,6,) with the same illumination zone to detection zoneradial distance as the first and second photon pathways, p₁₋₂, have meanphoton pathways that penetrate into the dermis 346 and not into thesubcutaneous fat 348. Thus, the water-to-fat ratio and/or theprotein-to-fat absorbance ratio of the observed signal continues toincrease with radial distance for the second and third detectors afterthe force system 200 increased the thickness of the dermis 346 to thesecond thickness, th₂.

Again, at least one preferred measurement/metric is a measurement with ahigher water-to-fat absorbance ratio and/or a higher protein-to-fatabsorbance ratio as the metric indicates that the photons are samplingthe dermis 346 without undue sampling of the subcutaneous fat 348, wherethe metric is used with or without an applied displacement force fromthe transducer. In this example, at the second time, the water-to-fatabsorbance ratio of the fifth optical path, p₅, is greater than observedwith the second optical path, p₂, despite have the same sourcezone-to-detector zone radial distance. Further, in this example apreferred optical signal is from the sixth optical path, th₆, at thesecond time, t₂, with a largest ratio of mean pathlength in the dermis346 to total mean detected pathlength. For illumination zone-to-detectorzone distances established to sample the dermis 346, as discussed infra,determining a current thickness of the protein/water rich dermis 346yields knowledge of an appropriate glucose illumination zone-to-glucosedetection zone, such as for photons in the range of 1500 to 1600 nm,probing the dermis 346 as glucose is soluble in the water rich dermis346.

Referring now to FIG. 7C, for clarity of presentation and without lossof generality, a particular metrics 760, such as a fat band metric, aprotein band metric, and/or a water band metric are illustrated. Asillustrated, a first signal 722 related to the fat absorbance band 720decreases in intensity with radial distance between an illumination zoneand a detection zone. The decrease in intensity with radius for a firstradial distance, r₁, a second radial distance, r₂, and a third radialdistance, r₃, relates dominantly to a decreased photon density as afunction of distance from the illumination zone, scattering, and waterabsorbance. However, a rapid first change in intensity, ΔI₁, is observedbetween the third radial distance, r₃, and the fourth radial distance,r₄, which at wavelengths related to the fat absorbance band 720, such asabout 1710 nm, indicates that a larger concentration of fat is observedto begin between the third and fourth radial distances indicating thatthe mean maximum depth of penetration of the probing photons has crossedfrom the dermis 346 into the subcutaneous fat 348. Hence, the largefirst change in intensity, ΔI₁, at the fourth radial distance indicatesthat a radial distance corresponding to a maximum depth of penetrationsampling the dermis 346 is the third radial distance, r₃. Similarly, thesecond signal 732 related to the water absorbance 710 and/or the proteinabsorbance 720 has a trend breaking second change in intensity, ΔI₂,between the third radial distance, r₃, and the fourth radial distance,r₄, which indicates that the second probing photons at a wavelengthdominated by a water absorbance, such as at 1450±10, 20, 30, 40, 50, 60,or 70 nm, or a protein absorbance, such as at 1690±5 or 10 nm, areobserving a lower concentration of the water and/or protein, such as bycrossing the same dermis—subcutaneous fat interface. Hence, any of themetrics related to water, protein, and/or fat are used independentlyand/or in any mathematical relationship, such as a ratio or derivative,to find a first sample probe geometric distance, between a firstillumination zone and a first detection zone, associated with a firstmaximum mean depth of penetration in the glucose rich dermis layer 346,such as at the first radius, r₃, and/or a second sample probe geometricdistance associated with a second maximum mean depth of penetration inthe glucose poor subcutaneous fat layer 348, such as at the fourthradius, r₄.

FIG. 7D illustrates increased scattering with decreasing wavelength at afirst scattering coefficient, μ_(s1), 740 and a second scatteringcoefficient, μ_(s2), 750. Optionally and preferably, an expecteddecrease in observed intensity with increasing radial distance between agiven illumination zone and a given detection zone includes use of ascattering coefficient, which is wavelength dependent.

EXAMPLE II

Referring now to FIG. 8, a second example is provided where the analyzer110 uses the force system 200 to alter the sample 300 to enhance anoninvasive analyte property determination using the spectrometer 140.As above, the force system 200 provides one or more force waves 250 intothe subject 320, which alters positions of cells 260 in the dermis 346relative to the illumination zone of the illumination system 400 and orrelative to one or more detection zones associated with a single elementdetector and/or one or more detectors of an array of detector elements510. As illustrated, the cells 360 have a first average intercellulardistance at a first time, t₁, which is altered by application of theforce wave 250 to a second average intercellular distance at a secondtime, t₂, where the net change in cell position alters detectedspectrophotometric absorbance signals at a give detector element of thedetector system 500 by greater than 0.01, 0.02, 0.05, 0.1, 0.5, 1, 2, 5,or 10 percent, such as by a change in observed scattering and/orobserved absorbance at a fixed radial distance between an illuminationzone and a detection zone. Similarly, the average percentage volume ofthe intercellular fluid 350 in the dermis layer differs by greater than0.01, 0.02, 0.05, 0.1, 0.5, 1, 2, 5, or 10 percent as a result of theapplied force wave(s) 250.

All of a change in thickness, change in observed mean pathlength, changein radial distance of detection, change in mean intercellular spacing,change in scattering, and change in water concentration, related toperfusion, are illustrated between the first time, t₁, and the secondtime, t₂, as a result of the applied force wave 250. Notably, a selecteddetector signal from the array of detectors 510 changed from a seconddetector element 512 at a first radial distance, r₁, from theillumination zone to a fourth detector element 514 at a second radialdistance, r₂, from the illumination zone based on the above describedlarger observed water signal-to-observed fat signal ratio and/or as thesecond pathlength, b₂, is longer than the first pathlength, b₁, in thedermis layer. Similarly, absorbances of skin constituents, such asprotein, albumin, globulin, keratin, and/or elastin increase relative tofat absorbance for the second pathlength, b₂, as the mean pathlengthspends more time in the dermis layer compared to the subcutaneous fatlayer 348, as described supra.

EXAMPLE III

Referring now to FIG. 9, a third example of using the force system 200to alter properties of the subject 330 to enhance performance of anoninvasive glucose concentration determination using the spectrometer140 is provided. In this example, the detector array 510 of the detectorsystem 500 contains n detector elements at differing radial distancesfrom a time correlated illumination zone. For clarity of presentation,the detector array 510 is illustrated with four detector elements: afirst detector element 511, a second detector element 512, a thirddetector element 513, and a fourth detector element 514. At a firsttime, t₁, the large water absorbance, protein absorbance, and/or proteinand water absorbance-to-fat ratio is observed using the second detectorelement 512 having a first illumination zone-to-detection zone radialdistance, r₁, and a first mean optical pathway, d₁, penetrating into thedermis 346 with minimal to no mean penetration into the subcutaneous fat348. However, at a second time, t₂, after the provided force wave 250has altered the skin of the subject 320, the third detector element isobserved, at a selected detection point in time, to have the largestmetric for detector selection, such as a smoothly falling observedintensity with radial distance at a fat absorbance wavelength, where asudden decrease in observed intensity at the fat absorbance wavelengthindicates mean penetration of the observed optical pathway into thesubcutaneous fat 348, such as at the second radial distance, r₂.Notably, the largest radial distance is selected for a given water,protein, and/or fat based metric as at the larger radial distance adifference between a shortest possible pathlength between theillumination zone and the detection zone, the radial distance, isclosest to the largest possible observed pathlength, which is based upona maximum observable absorbance by a detector type for a fixed number ofphotons. For example, if the maximum observable absorbance is 3.9 andthe absorbance per millimeter is 1.3, then a maximum observablepathlength is 3.0 mm. If the observed radial pathlength is 1.5 mm then afirst range of observed pathlengths is 1.5 to 3.0 mm with a differenceof 1.5 mm. Hence, a first ratio of observed pathlength difference toradial distance is 1:1 (1.5 mm:1.5 mm), which is a 100% error. However,if the observed radial pathlength is 2.5 mm, then a second range ofobserved pathlengths is 2.5 to 3.0 mm with a difference of 0.5 mm.Hence, a second ratio of observed pathlength difference-to-radialdistance is 1:5 (0.5 mm:2.5 mm), which is a second pathlength error of20% or one-fifth of the pathlength error of the first case. In general,the largest radial distance yielding and intensity-to-noise ratio beyonda threshold, such as 0.5, 1, 1.5 or 2, is preferred as error in a rangeof observed pathlengths decreases, which reduces the error in b, inBeer's Law: equation 1,

A=molar absorptivity*b*C   (eq. 1)

where A is absorbance, b is pathlength, and C is concentration, which iscentral to visible and near-infrared absorbance and/or scattering modelsused to determine an analyte property, such as a noninvasive glucoseconcentration as measured using photons optically probing skin.

Skin State Classification

Skin state is optionally classified using a single force pulse or singleimpulse function, also referred to herein as a ping. Generally, anapplied force, such as the force wave 250 provided by the force system200, takes time to propagate through the subject 320. The travel time ofthe force wave varies as a function of state of the body, such ashydration, temperature, glucose concentration, triglycerideconcentration, hematocrit and/or any constituent of skin, blood, and/orinterstitial fluid. Hence, the amount of time to travel radial distancesto force wave detectors is optionally used to classify the state of thesubject and/or to map the state of the subject in regions probed by theforce wave. For clarity of presentation and without loss of generality,two example of force wave detection are provided here using: (1) atransducer force detector and/or (2) an optical force wave classifier.

EXAMPLE I

Referring now to FIGS. 10(A-C), transducer force detectors areoptionally used to detect transit times of the force wave 250 from theforce wave input element 210 to one or more detectors of a set oftransducer force detectors 260. Generally, a transducer force detectorconverts mechanical motion, such as passage of the force wave 250 and/orskin movement into a measured electrical signal. Referring now to FIG.10A, for clarity of presentation and without loss of generality, a firsttransducer force detector 262, a second transducer force detector 264,and a third transducer force detector 266 are illustrated that representn transducer based force detectors, where n is a positive integer ofgreater than 1, 2, 3, 5, 10, or 20. As illustrated in FIGS. 10B and 10C,the n transducer based force detectors are optionally positioned in alinear array, in a two-dimensional array, and/or along arcs, such as atdiffering radial distances from one or more light sources in the sourcesystem 400. Referring still to FIG. 10A, as illustrated, at a firsttime, t₁, the force wave 250 has propagated to the first transducerforce detector 262 as a first wave front position 254; at a second time,t₂, the force wave 250 has propagated to the second transducer forcedetector 264 as a second wave front position 256; and at a third time,t3, the force wave 250 has propagated to the third transducer forcedetector 266 as a third wave front position 258. Timing of each wavefront to each transducer based force wave detector allows: (1)generation of a sub-surface tissue map of constituents of the skin ofthe subject 320 using mathematical techniques used for seismic mappingknown to those skilled in the art of seismic mapping and/or (2) aclassification of state of the subject 320 versus a calibration set ofclassifying states of force wave propagation radial translation times.For instance, the classification is as simple as slow, medium, or fasttranslation times to a given transducer detector or a more involvedcombination of translation times for one or more of: (1) responses at asingle detector position and (2) responses at a set of detectorpositions and/or responses to varying inputs of the force wave, such astime, direction, amplitude, and/or frequency of one or more pings fromthe force wave input elements and/or time varying induced appliedpressure and/or displacement of a portion of the skin of the subject 320by the force system 200.

EXAMPLE II

Referring now to FIGS. 11(A-C), propagation of the force wave(s) 250,such as force wave fronts 254, 256, 258 is detected using a set ofoptical detectors and using the results in a manner similar to detectingthe force wave 250 using the set of transducer based wave detectors. Forinstance, as the force wave 250 propagates through the tissue layers340, the density, absorbance, and/or scattering of voxels of the skin ofthe subject 320 change, which alters an observed mean optical pathbetween a given source of photons and a photon/photonic detector. One ormore sources of the source system 400 coupled to the array of opticaldetector elements 510 via the subject 320 is optionally used to detectpropagation times of the force wave(s) 250. For clarity of presentationand without loss of generality, a first optical detector 521, a secondoptical detector 522, and a third optical detector 523 are illustratedthat represent n optical detectors, where n is a positive integergreater than 0, 1, 2, 3, 5, 10, 15, 16, 20, 25, 100, 500, 1000, and5000. As illustrated in FIGS. 11B and 11C, the n optical detectors areoptionally positioned in a linear array, in a two-dimensional array,and/or along arcs, such as differing radial distances from one or morelight sources in the source system 400 and/or from one or more forcewave sources. Notably, one or more detectors of the array of opticaldetector elements 510 are optionally and preferably used to detectphotons from the source system 400 during a measurement phase of ananalyte and/or tissue property with or without a tissue classificationstep. As illustrated, the first optical detector 521 detects a firstoptical signal, modified by the force wave 250, with a first pathlength,p₁, at a given point in time; the second optical detector 522 detects asecond optical signal, modified by the force wave 250, with a secondpathlength, p₂, at the given point in time; and the third opticaldetector 523 detects a third optical signal, modified by the force wave250, with a third pathlength, p₃, at the given point in time. Eachdetected optical signal contains absorbances due to any sampleconstituent, such as water, protein, fat, and/or glucose and/or isrepresentative of state of the tissue, such as a measure of scatteringand/or temperature. As the force wave(s) propagate through the tissue,the first, second, and third pathlengths, p₁, p₂, p₃, vary. Hence, thestate of the subject 320 is optionally characterized and/or mapped in amanner similar to the transducer wave detection classification and/ormapping; however, optical signals with chemical meaning are used in theprocess, such as detected intensity, absorbance, and/or scatteringrelated to temperature, one or more tissue layer properties, collagen,elastin, water, albumin, globulin, protein, fat, hematocrit, and/orglucose, such as a concentration, change in tissue state, or a physicalstructure.

Referring again to FIG. 11A and FIG. 12A, the applied pressure/forcewave/displacement optionally generates a gap and/or varies an appliedpressure at a first interface 305 of the source system 400 and the skinsurface 330 and/or at a second interface 390 of the detector system 500and/or any element thereof and the skin surface 330. A resulting air gapbetween the analyzer 110 and the subject 320 and/or a time varyingchange between an air gap and contact between the analyzer 110 and thesubject 320 is used to determine times of contact/relative contact,which is in turn optionally and preferably used in a selection ofdetected signals step, described infra. For example, loss of opticalcontact yields a sudden increase in observed intensity in a wavelengthregion of high absorbance, such at as region dominated by waterabsorbance in the range of 1350 to 1550 nm, 1400 to 1500 nm, and/orwithin 5, 10, 15, 25, and/or 50 nm of 1450 nm. Removal of non-contactingsignals aids in the development of an outlier analysis algorithm and/orin determining state of the tissue and/or in determination of a degreeof applied force from the source system 400, detector system 500, and/oranalyzer 110 to the skin surface 330 of the subject 320 as a function oftime and/or position.

Force Wave/Optical Probe Analyte State Determination

Referring now to FIG. 12, a process of determining an analyte property,such as a glucose concentration, using one or more optical signalsoptionally and preferably modified by an applied force, force wave,and/or displacement is provided.

Referring still to FIG. 12, in a process, such as a first process or asecond process, a force is applied 1210, such as in the form of a forcewave and/or displacement induced force wave. For example, the forcewave/displacement is generated with a transducer to generate applicationof a transducer force 1212, which is a single ping 1214/displacementand/or a series of pings and/or is a force/displacement varied infrequency 1216 and/or varied in amplitude 1218, such as via acontroller, such as a main controller of the analyzer 110. Subsequently,the force wave 250/tissue displacement induced pressure propagates inthe sample 1220.

Referring still to FIG. 12, in another process, such as a first orsecond process, a result of the tissue displacement induced force waveis measured and/or detected 1230, such as through a transducer forcedetection 1232 and/or an optical force detection 1234.

Referring still to FIG. 12, in still another process, such as a secondand/or third process, selection of a sub-set of detected signals 1240 isperformed, such as a function of position 1241, time 1242, detector1243, contact 1244, pressure 1245, and/or spectroscopic response 1246and an analyte state is determined 1250, such as via generation of acalibration 1252 and/or use of a generated calibration in a predictionstep 1254.

Multiple-Sensor System

Referring again to FIG. 4A and referring now to FIG. 13, the analyzer110 optionally comprises multiple sub-sensor systems that operateindependently to collect data but operate in concert for determinationof state of the subject 320. For instance the spectrometer 140optionally comprises a first spectrometer version/system 142connected/affixed to a first part of the subject 320, such as on the armof the subject 320, and a second spectrometer system/version 144connected/affixed to a second part of the subject 320, such as on theleg of the subject 320. Optionally, the spectrometer 140 is affixed toany part of the body, such as an ear lobe, webbing of the hand,forehead, torso, limb, arm, or leg.

Still referring to FIG. 13, generally, the spectrometer 140 refers to nspectrometers/analyzers, where each of the n spectrometers optionallyand preferably collects data independently, where n is a positiveinteger, such as 1, 2, 3, 4, 5, or more. Optionally, each of the nspectrometers collect and analyze data independently. However,preferably, each of the n spectrometers collect data and after little orno pre-processing, collected data is sent to the analyzer 110, a centralprocessor, a personal communication device, such as a cell phone 122,and/or to the web for further processing, which allows a central systemto process data from the multiple sub-spectrometer systems.

Still referring to FIG. 13, optionally, each of the n spectrometers areof the same type and design. However, preferably, each of the nspectrometers are distinct in type and/or design. For instance, thefirst spectrometer version 142 comprises first sources, optics, anddetectors that are directed to measurement of a firstconstituent/property of the subject 320 and the second spectrometerversion 144 comprises second sources, optics, and detectors that aredirected to measurement of a second constituent/property of the subject320.

Still referring to FIG. 13, for example, the n spectrometer systems areoptionally and preferably configured to interface to separate portionsof the body and/or to measure separate and/or overlappingproperties/constituents of the subject 320, such as percent oxygensaturation, heart rate, heart rate variability, glucose concentration,protein concentration, fat, muscle, protein concentration, albuminconcentration, globulin concentration, respiration rate, anelectrocardiogram, blood pressure, and/or body temperature and/orenvironmental temperature and/or acceleration of the subject 320, suchas to indicate a fall of the subject 320 and/or an interfering movementof the subject 320 that affects the measurements of the one or morespectrometers 140.

Still referring to FIG. 13, herein, for clarity of presentation andwithout loss of generality, the spectrometer 140 is illustrated as anoninvasive glucose concentration analyzer. However, the spectrometer140 optionally measures any constituent of the body noninvasively, in aminimally invasive manner, and/or operates in conjunction with anoninvasive, minimally invasive, and/or invasive reference system, suchas for calibration and quality control procedures.

Examples of a first spectrometer version 142 and a second spectrometerversion 144 determining an analyte property is provided, infra.

EXAMPLE I

Referring still to FIG. 13, an example of interfacing 1300 the analyzer110 to an arm 370 of the subject 320 is illustrated. As illustrated, afirst analyzer/spectrometer version 371 of the analyzer 110 is coupledto a section of an upper arm 372 of the subject's arm and a secondanalyzer/spectrometer version 373 of the analyzer 110 is coupled to aforearm/wrist 374 of the patient's arm 320. Notably, the first analyzerversion 371 interfaces to the subject 320 at a first interface zonealong a first z-axis perpendicular to a first x/y-axis plane that istangential to the subject 320 and that is independent and different froma second interface of the second analyzer version 373, which interfacesto the subject 320 along a second z-axis perpendicular to a secondx/y-axis system that is tangential to a second interface zone of thesubject. Generally, n analyzers 110, optionally linked to a single maincontroller 112, interface to n interface zones of the subject 320, wherethe main controller 112 is optionally and preferably electrically,mechanically, and/or communicatively linked with any and preferably allsubsystems of the analyzer 110 and is used to control the analyzer 110,such as via computer hardware and associated software.

EXAMPLE II

Still referring to FIG. 13, each of the analyzers interfacing to thesubject 320 optionally comprise any system of the analyzer 110. Asillustrated, the first analyzer version 371, which is an example of theanalyzer 110 comprises three analyzer versions, illustrated as the firstspectrometer version 142, the second spectrometer version 144, and thethird spectrometer version 146. As illustrated, the first spectrometerversion 142, optionally in the form of a watch head, interfaces to thesubject 320 along a first z-axis perpendicular to a first x/y-plane,which tangentially touches the upper arm 372 at a first interface point;the second spectrometer version 144 has the form of a watch band linkand interfaces to the subject 320 along a second z-axis perpendicular toa second x/y-plane, which tangentially touches the upper arm 372 at asecond interface point; and the third spectrometer version 146,optionally in the form of a watch band attachment, interfaces to thesubject 320 along a third z-axis perpendicular to a third x/y-plane,which tangentially touches the upper arm 372 at a third interface point.Each of the three spectrometer versions 142, 144, 146 are optionallyattached to the upper arm 146 via double-sided adhesives and are thusattached in the manner of a sticker. As illustrated, the threespectrometer versions 142, 144, 146 are attached to the upper arm 372with a flexible band 148, such as a watch band or an elastic band. Theindividual spectrometer versions 142, 144, 146 are optionally connectedusing one or more hinge components and or rotating connectors. Theindividual spectrometer versions 142, 144, 146 are optionallyreplaceably connected to the subject along separate planes formingangles therebetween of greater than 1, 2, 5, 10, 15, 25, or 25 degrees.The hinge allows tangential interfacing of illumination zones of therespective spectrometer version along a curved surface of the subject320. Optionally, the hinge allows for rotation of a first spectrometerunit relative to a second spectrometer unit to maintain tangentialcontact of the illumination zones with the subject 320 as the skin ofthe subject moves, such as by allowing a rotation of greater than 0.1,0.5, 1, 2, or 5 degrees. The multiple planes of attachment of theanalyzer 110 to the subject 320 allow attachment of multiple sourcesand/or detectors to the subject 320 along a curved skin surface of thesubject 320, such as around the upper arm 372 and/or the lower arm 374,as illustrated with the second analyzer/spectrometer version 373attached to the wrist of the subject 320, with minimal applied tissuedeformation forces at each of the analyzer/subject interface zones.Reduced forces, such as an applied mass, stress, and/or strain aidsprecision and/or accuracy of the analyzer 110 by reducing movement offluids within the tissue layers 340 of the subject 320, reducing changesin pathlength, and/or reducing changes in pressure induced scattering oflight.

EXAMPLE III

Still referring to FIG. 13, in a first case, each of the firstspectrometer version 142, second spectrometer version 144, and thirdspectrometer version 146 optionally contain all of the functionality ofthe analyzer 110. However, optionally, one or more optical sources arein one interfacing aspect of the first analyzer version 371, such as inthe second spectrometer version 144, without any functional opticaldetectors in the second spectrometer version 144. In this case, theoptical detectors are in a second interfacing aspect of the firstanalyzer version 371, such as in the first spectrometer version 142. Forclarity of presentation and without loss of generality, a particularexample is provided. In this example, the detector system 500 ispositioned in the analyzer 110 in the first spectrometer version 142along with optional illuminators of the source system 400. However, thesource system also includes photon sources in the second spectrometerversion 144, such as in a watch band link position. In this manner,photonic illuminators with short optical distances to the detectorsystem 500 are positioned in the first spectrometer version 142, such asin close proximity to the detector system 500. For instance, photonicsources emitting in wavelength ranges: (1) with an optical absorbance ofgreater than one unit per millimeter of pathlength and/or (2) in the1350 to 1560 nm range, such as within 25 mm of 1510, 1520, 1530, or 1540nm are positioned near the detector system 500, such as in the samehousing as the detector system 500, in the first spectrometer version142, and/or with a radial distance between an illumination zone and adetection zone of less than 10, 8, 6, 5, 4, 3, 2, 1.5, or 1 millimeters.However, photonic sources emitting in lower absorbance regions, such asfrom 400 to 1350 nm and/or 1565 to 1800 and/or in regions of absorbanceby skin at a level of less than one absorbance unit per millimeter ofpathlength are positioned in the second spectrometer version 144, thusgiving the photons a longer pathlength to the detector system 500 in thefirst spectrometer version 142. The longer selected pathlength, asselected by a detector element of the detector system 500, from a givensource reduces a range of observed pathlengths by photons from the givensource, as described supra. Further, each spectrometer version 142, 144,146 allows an independent mean photon path entering the skin of thesubject 320 to be perpendicular to the subject 320 despite the radius ofcurvature of the skin of the subject 320 as the differing spectrometerversions 142, 144, 146 are each positioned with an x/y-plane interfacetangential to the local curvature of the skin of the subject 320, suchas at different positions on a watch band equivalent. Optionally andpreferably, the x/y-planes tangential to the subject 320 at local sampleinterface sites for the n interface points of the analyzer 110, such asthe first interface location of the first spectrometer version 142, thesecond interface location of the second spectrometer version 144, andthe third interface location of the third spectrometer version 146 areseparated by greater than 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20millimeters as measured along the skin surface. Hence, second photonsources for providing second wavelengths for measuring oxygen and/orscattering of light, such as from 400 to 1300 nm, are optionally placedin a second housing along a second position of the watch band whilefirst photon sources for providing first wavelengths, such as at glucoseabsorbing wavelengths from 1500 to 2400 nm, are optionally placed in afirst housing proximate detector elements, where the detector elementsin the first housing detect photons from second, third, . . . , n^(th)housings, such as along a circumferential band around a curved bodypart, where n is a positive integer greater than 1, 2, or 3.

EXAMPLE IV

In the first spectrometer version 371 of the analyzer 110, three sampleinterface zones are used, a first sample interface zone, such as theback of a watch zone where the source system 400, force system 200,and/or a first set of optics, such as in the first spectrometer version142, interface to the subject 320; a second interface zone, such aswhere a second set of optics, such as in the second spectrometer version144, interface to the subject 320; and a third interface zone, such aswhere a third set of optics, such as in a third spectrometer version146, interface to the subject 320. Generally, any number n of sets ofoptics interface to the subject 320 to yield n sets of data on a stateof the subject 320 where n is a positive integer, such as 1, 2, 3, 4, 5or more. Optionally, the n sets of optics generate simultaneous data ona single state of the subject 320. However, each sub-set of optics inthe n sets of optics are optionally configured to measure the sameanalyte and/or different analytes, such as one of more of percent oxygensaturation, heart rate, heart rate variability, glucose concentration,protein concentration, fat, muscle, protein concentration, albuminconcentration, globulin concentration, respiration rate, anelectrocardiogram, blood pressure, body temperature, environmentaltemperature, and acceleration of the subject 320.

Depth Resolution

Photons scatter in tissue. However, a mean photon path between anillumination zone and a detection zone has a mean/medium/average depthof penetration into the skin layers 340 and glucose is present atdiffering concentrations as a function of depth into the skin layers340. A target zone of probing photons is the epidermis 344 and/or dermis346 between the stratum corneum 342 and the subcutaneous fat 348.Targeting these well perfused tissue layers is described herein by wayof non-limiting examples.

EXAMPLE I

Referring now to FIG. 14A, an example of a probe tip 1400 of the sourcesystem 400 of the analyzer 110 is presented. The probe tip 1400 has atissue contacting surface 1410 and at least one illumination zone of aset of illumination zones 1420. For clarity of presentation and withoutloss of generality, a single illumination zone is illustrated which isoptionally and preferably one illumination zone of a plurality ofillumination zones, such as where a given illumination zone is a surfacearea of the skin/probe tip interface illuminated by a given source, suchas a given light emitting diode. More particularly, 2, 3, 4, or 5, ormore, light emitting diodes/laser diodes couple to the skin, optionallyvia intervening optics of the photon transport system 450, to illuminatea corresponding second, third, fourth, and fifth, or more, skin/probetip interface areas, referred to herein as illumination zones.Similarly, a given detector element optically couples, such as by thephoton transport system 450 to a given surface area of the skin/probetip interface, which is referred to as a detection zone. Moreparticularly, 2, 3, 4, or 5, or more, detector elements, of the detectorsystem 500, optically interface, such as through optics of the photontransport system 450 with the skin, to detect photons emitting from acorresponding second, third, fourth, and fifth, or more, skin/probe tipinterface area, referred to herein as detection zones. A mean opticalpath for a set of photons is a mean pathway through the tissue layers340 of the subject 320 between a given illumination zone and a givendetection zone. Optionally, the probe tip 1400 is of any geometry.Optionally, illumination zones are of any pattern on the probe tip 1400.Optionally, detection zones are of any layout on the probe tip 1400.

EXAMPLE II

Referring still to FIG. 14A and referring now to FIG. 14B, resolution ofa mean depth of penetration of probing photons between an illuminationzone and rings of detectors 1430 is provided. As illustrated, a firstring of detectors 1432, coupled to a first set of detection zones, is ata first radius, r₁, from the illumination zone and a second ring ofdetectors 1434, coupled to a second set of detection zones, is at asecond radius, r₂, from the illumination zone. For clarity ofpresentation and without loss of generality, the detectors and detectorzones are illustrated with the same circular graphical representationherein. Further, the circular graphical representations are optionallyillustrative of the ends of fiber optics coupled to correspondingdetectors or sources. At close distances having an observed absorbanceof less than one, the mean depth of penetration of probing photonsincreases with radial distance. The first and second ring of detectors1432, 1434 are separated by a radial distance difference, Δr₁. Referringnow to FIG. 14B, the first ring of detectors 1432 corresponds to a firstmean optical path 1472 having a first depth of penetration into thetissue layers 340 and the second ring of detectors 1434 corresponds to asecond mean optical path 1474 having a second depth of penetration intothe tissue layers 340. As illustrated, for a first radial detector 1482at the first radial distance, r₁, the maximum depth of the first meanoptical path 1472 and the second mean optical path, for a second radialdetector 1484 at a second radial distance, r₂, have a depth ofpenetration difference, Δd₁. Notably, the second ring of detectors 1434is spatially positioned at a closest linear distance, the line passingthrough an illumination zone of the set of illumination zones 1420, tothe first ring of detectors 1432. Thus, the best resolution of depth isthe depth of penetration difference, Δd₁, corresponding to a first rangeof tissue thicknesses 1482. However, in many cases, as the thicknessesof the epidermis 344 and dermis 346 changes with applied pressure,force, hydration, spatial orientation, movement, and/or changes in bloodconstituent concentration, the targeted dermal layers are not resolvedusing the best resolution of concentric detector rings with a differencein radial distance, Δr₁, to the illumination zone corresponding to theresolved depth, Δd₁.

EXAMPLE III

Referring still to FIG. 14A and FIG. 14B and referring now to FIG. 14C,a comparison of resolution of a mean depth of penetration of probingphotons between an illumination zone and rings of detectors 1430 andarcs of detectors 1450 is provided. Herein, an arc of detectors is a setof detectors along a curved path of multiple radial distances from anillumination zone. The arced path is not an arc of a circle. Rather, thearced path is along a spiral and/or curve covering a range of radialdistances from an illumination zone. As illustrated an arc of detectors1450, along an optional arc layout 1462, starts at the first radialdistance, r₁, of the first ring of detectors 1432 and ends at the secondradial distance, r₂, of the second ring of detectors. While the firstand second ring of detectors have a first linear radial distancedifference, r₁, that is based on the size of the detector elementhousing, fiber optic, and/or detection zone, the illustrated arc ofdetectors 1450 has a second linear radial distance difference, r₂, thatis smaller than, r₁.

Particularly, with the seven illustrated detectors in the arc ofdetectors, the second linear radial distance, r₂, is one-seventh that ofthe first radial distance, r₁. Generally, the difference in radialdistance is better than ½, ⅓, ¼, ⅕, . . . , 1/n that of the spatiallyconstrained concentric rings of detectors for n detector elements in anarc bounded by the first and second radial distances, r₁ and r₂, of theconcentric rings of detectors, where n is a positive integer of greaterthan 2, 3, 4, 5, 10, or 20. Comparing now the first and second meandepths of penetrations 1472, 1474 for the first and second ring ofdetectors 1432, 1434 and the first and second detector 1482, 1484, withthe range of mean depths of penetrations in FIG. 14C corresponding tothe individual illumination zones, of the set of illumination zones1420, to detection zones of detector elements in the ring of detectorelements 1450, the enhanced resolution is illustratively obvious.Particularly, the above described first resolved depth, Δd₁,corresponding to the first and second ring of detectors 1432, 1434 isseven times larger than a second resolved depth, Δd₂, between a thirdmean path 1437 and a fourth mean path 1474 corresponding to the secondradial detector 1484 and a closest intermediate radial detector 1486,two detector elements in the arc of detectors 1450. Particularly, asecond range of tissue thicknesses 1484 is thinner than the first rangeof tissue thicknesses 1482, described supra. Generally, the differencein resolved tissue depth is better than ½, ⅓, ¼, ⅕, . . . , 1/n that ofthe spatially constrained concentric rings of detectors for n detectorelements in an arc bounded by the first and second radial distances, r₁and r₂, of the concentric rings of detectors, where n is a positiveinteger of greater than 2, 3, 4, 5, 10, or 20. Thus, arcs of detectionzones corresponding to arcs of detectors and/or coupling optics, such asfiber optics, spanning a range of radial distances from an illuminationzone yield an enhanced resolution of tissue depth. Further, as describedsupra, dynamic selection of signals from detector elements radiallyinward from an outwardly positioned detector element observing adisproportionate increase in a fat band absorbance, which is an exampleof a spectroscopic marker, from the subcutaneous fat 348, at a greaterdepth than the targeted dermis 346, yields the largest radial distanceobserving the desired/targeted dermal layers. Further, as the epidermis344 and dermis 346 change in thickness, such as due to subject movement,orientation, and/or hydration, and/or changes in body chemistry, therange of resolved depths of penetration corresponding to the range ofradial distances between the illumination zone and individual detectionzones allows dynamic selection of source-to-detector distances currentlyprobing the desired dermal layers, such as the epidermis 344 and thedermis 346.

Depth/Location Selection

Referring now to FIGS. 15A, 15B, 15C, 15D, 16A, 16B, 16C, 16D, and 17, amethod and apparatus are described for selecting, as a function ofwavelength, illumination zone-to-detection zone distances yielding acommon and/or overlapping depth of sampling and/or position of sampling.In the examples provided, for clarity of presentation and without lossof generality, notation of a first, second, third, . . . , n^(th) sourceand/or detector is used where the n^(th) source/detector in one exampleis optionally distinct from the n^(th) source/detector in anotherexample. Further, it is understood that skin layers are not homogenousand that variations occur from tissue voxel to tissue voxel. However,sampling a common depth and location aids in measuring a common samplestate within the non-homogenous tissue layers, especially when used inconjunction with one or more of: a larger illumination zone, a largerdetection zone, sample movement relative to the analyzer, and/oranalyzer movement relative to the sample.

EXAMPLE I

Referring now to FIG. 15A, FIG. 15B, FIG. 15C, and FIG. 15D in thisfirst example, a common depth selection system 1500 and method of usethereof is described.

Referring now to FIG. 15A. The spectrometer includes a first source401/source element, illuminating a first illumination zone of the set ofillumination zones 1420.

Light from the first illumination zone is detected by a first set ofdetectors 1510, such as a first detector 511 detecting photons at afirst detection zone, a second detector 512 detecting photons at asecond detection zone, a third detector 513 detecting photons at a thirddetection zone, and/or a fourth detector 514 detecting photons at afourth detection zone. Herein, the sources and detectors are illustratedat the skin surface for clarity of presentation and without loss ofgenerality. However, it should be understood that the actual sourceand/or detector elements, are optionally positioned anywhere, and areoptionally and preferably optically coupled to their respective sourcezone/detection zone via air and/or one or more optics. For instance, asource optionally uses a fiber optic, or any optic, to deliver lightfrom the source to the outer skin surface 330. Similarly, a detectoroptionally uses any optic to deliver a portion of the photons emittingfrom a detection zone, optically visible to the detector, to thedetector element.

Referring still to FIG. 15A and referring now to FIG. 15B, depths ofpenetration of photons passing from the set of illumination zones 1420to the second set of detectors 1520 is illustrated. As illustrated,photons have a first mean path, p₁, from the first illumination zoneassociated with and/or optically linked to the first source 401 and to afirst detection zone associated with and/or optically linked to thefirst detector 511. Similarly, as illustrated, photons have a secondmean path, p₂, from the first illumination zone associated with and/oroptically linked to the second source 402 and to a second detection zoneassociated with and/or optically linked to the second detector 512.Similarly, a third mean path, p₃, and fourth mean path, p₄, link thethird detector 513 and fourth detector 514 to the first source 401. Itshould be understood that the actual mean optical paths are not cleararcs as illustrated and the mean paths rather illustrate the point thatdiffering illumination zone-to-detector zone distances have differingcoupling mean pathways and/or the pathways probed differing samplelayers at different weights. As illustrated, the second mean path, p₂,is the longest path in the dermis layer 346 that does not substantiallypass through the subcutaneous fat layer 348, which is a first selectionmetric, which is an example of a selection metric. In this example, thesecond mean path, p₂, is a first selected path based upon the selectionmetric. Selection metrics are optionally generated using one or morereadings related to absorbance of fat, water, and/or protein. It shouldbe understood that the first source 401 is illustrated at a firstillumination zone only for clarity of presentation and the first sourceis optionally and preferably embedded into the analyzer 110 and coupledto the illustrated illumination zone with or without a coupling opticand that this general presentation approach holds for each source andsimilarly holds for each detector where a given detector is illustratedat a detection zone where optionally and preferably the given detectoris configured to view the detection zone with or without an interveningoptic.

Referring still to FIG. 15A and FIG. 15B, depths of penetration ofphotons passing from the set of illumination zones 1420 to the secondset of detectors 1520 is further described for a second wavelengthrange, where photons from the first source 401 have a first distributionof intensity as a function of wavelength and a first mean wavelength andphotons from a second source 402 have a second distribution of intensityas a function of wavelength and a second mean wavelength differing fromthe first mean wavelength by greater than 1, 2, 5, 10, 20, 50, or 100nm. Photons from the second source 402 interact with tissue differentlyfrom the photons from the first source 401, in terms of absorbance andscattering, which results in differing total pathlengths and samplepathlength in tissue layers, such as the epidermis 344, dermis 346,and/or subcutaneous fat 348. As illustrated, a second set ofwavelengths, from the second source 402, reaching the surface of theskin 330 have longer observed mean pathlengths than a first set ofwavelengths, from the first source 401, reaching the outer skin surface330 or surface of the skin. For instance, the second set of wavelengthscover a wavelength range with lower overall absorbance of the sampleconstituents, such as a lower water absorbance, than the first set ofwavelengths. As above, photons from the second source 402 have a fifthmean optical path, p₅, /fifth path/fifth mean path; a sixth mean path,p₆; a seventh mean path, p₇; and an eighth mean path, p₈, to a fifth,sixth, seventh, and eighth detection zone observed by a fifth detector515, a sixth detector 516, a seventh detector 517, and an eighthdetector 518, respectively. Generally, any number of sources, m; anynumber of detectors, n; and/or any number of radial distances, r, areoptionally used, where m and n are positive integers and r is a distanceof greater than 0.01, 0.1, 0.5, 1, 1.5, 2, 3, 4, 5, or 10 millimeters.

Still referring to FIG. 15A and FIG. 15B, using the same criteria of thelongest observed path in the dermis layer 346 that does notsubstantially pass through the subcutaneous fat layer 348, the seventhpath, p₇, is a second selected path based upon the first selectionmetric. The first selected path, p₂, and the second selected path, p₇,are both weighted to a common sample depth, the dermis 346. Hence, (1)the first source 401 coupled to the second detector 512 and (2) thesecond source 402 coupled to the seventh detector 517 each have weightedsampling to a common sample, the dermis 346. In stark contrast, at acommon radial distance, such as observed at the first detector 511 andfifth detector 515, the mean photons sample differing samples; the firstsource 401 dominantly sampling both the epidermis 344 and dermis 348, asillustrated by the first path, p₁, and the second source 402 dominantlysampling the epidermis 344, as illustrated by the fifth path, p₅.

Referring now to FIG. 15C, the chosen radial separations of the sourcesand detectors, such as chosen in the preceding paragraph of this firstexample, are illustrated in an optional second probe configuration 1502.Particularly, (1) a first selected radial distance, r₁, between thefirst source 401 and the selected second detector 512 is maintained and(2) a second radial distance, r₂, between the second source 402 and theselected seventh detector 517 is maintained without the need of theadditional detector elements. Thus, for a static sample, the benefits ofthe common depth selection system 1500 are maintained in the secondprobe configuration 1502.

EXAMPLE II

Referring now to FIG. 16A, FIG. 16B, FIG. 16C, and FIG. 16D in thissecond example, a common sample position selection system 1600 andmethod of use thereof is described, where the common sample position isoptionally and preferably at the common depth, such as the dermis,described supra.

Referring still to FIG. 16A and FIG. 16B, the common sample positionsystem 1600 is first described through an illustrated addition of twoadditional wavelength ranges to the common depth selection system 1500,described supra, where the resulting four wavelength ranges have fourdistinct mean wavelengths reaching the detector and where each of thefour distinct mean wavelengths are separated from each other by at least10 nm. Particularly, the separation of the first source 401 from thesecond detector 512 by the first radial distance, r₁, is maintained fromthe prior example as is the separation of the second source 402 from theseventh detector 517 by the second radial distance, r₂. Added to theillustration is a separation of the third source 403 from the sixthdetector 516 by a third radial distance, r₃, and a separation of afourth source 404 from a ninth detector 519 by a fourth radial distance,r₄. Notably, all of the illustrated source-to-detector distances areselected, such as by the method of the first example and/or through useof a metric, such as a measure of water, protein, and/or fat absorbance,to sample a common depth, which as illustrated is the dermis 346. Anapparatus setting each of the four wavelength ranges to a same meanlateral x-position and/or y-position is described, infra.

Referring now to FIG. 16C and FIG. 16D, the four source-to-detectordistances, described supra, selected to sample a common depth, such asthe dermis, are positioned in a probe face to yield a common lateralposition at depth within the tissue or a common central zone 1610 at thesurface. Particularly, a mean position between each of thesource-to-detector positions is overlaid on at a common x-axis, asillustrated, and/or a common y-axis position to within less than 2, 1,0.5, 0.4, 0.3, 0.2, or 0.1 mm.

Referring now to FIGS. 15(A-D) and FIGS. 16(A-D), while skin is nothomogeneous, overlapping the photonic pathways of a set of differingwavelengths detected by a set of detectors, in terms of a common depthand/or a common position, yields a higher probability of sampling acommon tissue state.

EXAMPLE III

Referring now to FIG. 17, in this third example, a common depthselection and common detector system 1700 and method of use thereof isdescribed.

Still referring to FIG. 17, generally, different wavelengths of light,in the range of 1100 to 2500 nm, have different mean depths ofpenetration into skin due to skin having a large range of absorbanceand/or a large range of scattering as a function of wavelength. Forinstance, first photons at a first wavelength where the skin absorbsheavily, such as at and/or near a peak of the water absorbance bands710, at 1450 nm, and/or at 1900 nm, have a shallow maximum mean depth ofpenetration into the skin layers, such as only penetrating into theepidermis 344. Similarly, second photons at wavelengths having a lowerabsorbance, such as on a shoulder of the water absorbance bands 710,have a mean detected photonic path that penetrates deeper into the skin,such as into the dermis 346. Again similarly, third photons havingwavelengths at a still lower absorbance, such as at and/or near a valleyof the water absorbance bands 710, have a mean detected photonic paththat penetrates still deeper into the skin, such as into thesubcutaneous fat 348. Hence, traditional systems sampling differentwavelength ranges sample different mean sample depths.

Generally, a magnitude of absorbance of the skin is inversely related toa maximum mean depth of penetration of detected photons into the skinand water absorbance, optionally modified by scattering, dominates anoverall magnitude of absorbance of the skin due to waters highabsorbance in the range of 1100 to 2500 nm relative to other skinconstituents.

As a result of sampling differing sample depths, errors are introducedinto traditional analyzers, such as a noninvasive glucose concentrationanalyzer, as the skin layers 340 differ in both chemical and physicalmakeup and hence the wavelengths actually probe different samples. Here,a system of sampling a common skin layer is described, where optionallyand preferably signals with differing illumination zone-to-detector zonedistances are measured with a common detection zone optically linked toa detection system, such as a detector and/or a detector opticallycoupled to the common detection zone with one or more optics.

Referring again to FIG. 17, for clarity of presentation and without lossof generality, a specific case of a range of wavelengths sampling acommon skin layer is described. Particularly, in this case the firstsource 401 comprises a higher relative sample absorbance, such as within10, 20, 30, 40, 50, 75, or 100 nm of a peak water absorbance at 1450 or1900 nm and a first detected signal of photons from the first source 401is dominated by a water signal at a first radial distance, r₁, to thefirst detector 511, where the first radial distance is set at a distanceyielding a maximum mean photonic path in the dermis 346. Further, inthis case the second source 402 comprises a mid-range sample absorbance,such as within 10, 20, 30, 40, or 50 nm of a mid-point absorbance of thepeak water absorbance bands, such as at 1410, 1520, 1870, 2020, or 2380nm, where the second detected signal of photons from the second source402 is still dominated by a water signal at a second radial distance,r₂, but, the second wavelength range also samples another sampleconstituent, such as glucose, while still yielding a maximum meanphotonic path in the dermis 346. Notably, to sample the same depth asthe first illumination zone-to-detection distance, while being as asecond wavelength of lower overall absorbance, the second radialdistance is larger than the first radial distance. Still further, inthis case the third source 403 comprises a still lower sampleabsorbance, such as within 10, 20, 30, or 40 nm of a first quartilepoint of the peak water absorbance bands, such as at 1380, 1550, 1850,2090, or 2350 nm, where the third detected signal of photons from thethird source 403 is still dominated by a water signal at a third radialdistance, r₃, but, the third wavelength range also samples anothersample constituent, such as protein, while still yielding a maximum meanphotonic path in the dermis 346 by having the third radial distance belonger than the second radial distance, which is in turn larger than thefirst radial distance. Yet still further, in this case the fourth source404 comprises the still lower sample absorbance, such as within 10, 20,30, or 40 nm of the first quartile point of the peak water absorbancebands, such as at 1380, 1550, 1850, 2090, or 2350 nm, where the fourthdetected signal of photons from the fourth source 404 is still dominatedby a water signal at a fourth radial distance, r₄, but, the fourthwavelength range also samples another sample constituent, such as thesubcutaneous fat 348, by having the fourth radial distance be furtherfrom detection zone relative to the third radial distance. Stated again,although the third source 413 emits third detected photons at a higherwater absorbance wavelength/value relative to a lower waterabsorbance/value in a range of fourth detected photons, the maximum meandepth of the fourth photons penetrates further into the sample, such asthe subcutaneous fat 348 relative to the dermis 346 probed by the thirdphotons, due to the larger radial distance of the fourth radial distancerelative to the third radial distance. Optionally, the third radialdistance is configured to measure protein, such as at a wavelength with5, or 10 nanometers of 1690 nm. Optionally, the fourth radial distanceis configured to measure subcutaneous fat, such as at a wavelength with5 or 10 nanometers of 1710 nm.

Still referring to FIG. 7A, optionally, a common detection zone linkedto a common detector system is used to sample light from the first,second, third, and fourth radial distances from the first source 401,the second source 402, the third source 403, and the fourth source 404,respectively. Generally, targeting skin layers 340 is demonstrated foreach of a set of range of wavelength ranges, where each member of theset of wavelength ranges comprising a source-to-detector distance set byprior analysis, skin absorbance, water absorbance, and/or scattering.Notably, enhanced precision of depth targeting is achieved by measuringa range of illumination zone-to-detection zone distances. In thisexample, the higher relative absorbance is at least 20, 30, 40, 50, 75,or 100 percent higher than the mid-range absorbance. In this examplemid-range absorbance is at least 20, 30, 40, 50, 75, or 100 percenthigher than the lower quartile absorbance. In this example, the secondradial distance is at least 0.2, 0.3, 0.4, 0.5, 0.75, or 1 mm largerthan the first radial distance; the third radial distance is at least0.2, 0.3, 0.4, 0.5, 0.75, or 1 mm larger than the second radialdistance; and/or the third radial distance is at least 0.2, 0.3, 0.4,0.5, 0.75, or 1 mm larger than the fourth radial distance.

Optionally and preferably, the sources are light emitting diodes, laserdiodes, and/or provide a narrow band of light through use of a long passfilter, a short pass filter, a bandpass filter, and/or an opticalfilter. Generally, a given optional source system intended to illuminatea given wavelength region may provide additional photons at otherregions of higher water absorbance, where the water absorbance blocksthe additional photons. Generally, a given source intended to illuminatea given wavelength range, in the 1100 to 2500 nm wavelength region, doesnot provide more than 20, 10, 5, or 0 percent of the light in a lowerabsorbing region. For instance, a source intended to provide photons foranalysis of fat at 1710 nm may provide photons from 1700 to 1720 nm,where photons at 1900 to 2000 nm are optionally provided as they areabsorbed by water in the skin, and where photons at 1500 to 1650 nm areprovided only at low intensity or are optically blocked as the water ofthe skin allows more of the photons in the 1500 to 1650 nm region toreach the detector and are thus avoided for analysis of the fat.Similarly, each intend wavelength, for analytes such as water, protein,and glucose, have similar source requirements for a common detectorsystem. In an optional case where one or more detector systems hasblocking optics for different wavelengths, the limitations on the sourcesystems described herein is removed.

EXAMPLE IV

Referring now to FIG. 18, in this third example, a common depthselection and common sample position analyzer 1800 and method of usethereof is described. Generally, for each member of a set of sources acommon mid-zone 999 and/or mid-point to a detector for each source isused to provide a common/overlapping sample position. Further, a radialdistance for each source/detector combination is set according toabsorbance/scattering of the tissue. For instance, the first radialdistance, r₁, in the previous example for the first source 401 and thecommon detector 511 is maintained and used here for the distance betweenthe first source 401 and a first selected detector, 1d, /first selecteddetection zone to yield a maximum mean photonic path in the dermis 346,as described supra, for a water dominated wavelength, such as about1410±25 nm. Similarly, the second source 402, third source 403, andfourth source 404 are separated by the second, third, and fourth radialdistances of the previous example from a second selected detector, 2d, athird selected detector, 3d, and a fourth selected detector, 4d,respectively, which yields a common mean maximum sample depth, such asin the dermis 346. Combined, a common sample position and common depthsystem is illustrated as: (1) each source-to-detector distance comprisesa mid-point in the probe tip 1400 about a central samplinglocation/central sampling zone 999, which yields a common location and(2) the radial distances between a given illumination zone-to-detectionzone being set with radial distances based upon the wavelength yields acommon depth.

Still referring to FIG. 18, the mid-zone 999/sample zone is illustratedon a sample side face of a probe housing of the analyzer 110, such as ona surface of the probe tip 1400. When a linked illumination zone anddetection zone reside on opposite sides of the sample zone, a commonsampled tissue volume resides in the tissue on the z-axis down from thesample zone, such as if the illumination zone-to-sample zone distance iswithin ten or twenty percent of the sample zone distance-to-detectionzone distance.

Still referring to FIG. 18, selection of a common sample position andcommon depth is illustrated for a range of skin types/skin states.Through time, a given skin state changes from a thicker dermis to athinner dermis as a function of time or vise-versa, due to factors suchas age, temperature, hydration, and water shifting to thegastro-intestinal region for digestion of recently ingested food.Similarly, the transducer 220 is optionally used to dynamically changethe thickness of the dermis 346 as a function of time, such as describedsupra. Hence, a given illumination zone-to-detection zone distance for agiven source/detector combination for a given wavelength range isoptionally and preferably dynamically selected based upon the currentstate of the skin and/or the current state/thickness of the dermis 346.Particularly, for the first illumination zone-to-first detection zonedistance, a first set of detectors 1510 includes the first selecteddetector, 1d, set at the first radial distance, r₁, from the firstillumination zone associated with the first source 401, but alsooptionally and preferably includes a second optionally selecteddetection zone positioned radially inward from the first detector and athird optionally selected detection zone positioned radially outwardfrom the first detector, relative to the first illumination zone. As aresult, when the dermis 346 is thinner, the radially inwardly positioneddetection zone associated with the first set of detectors 1510 isselected/used to sample the dermis and when the dermis 346 is thicker,the radially outwardly positioned detection zone associated with thefirst set of detectors 1510 is selected/used to sample the dermis.Similarly, the second detector, 2d, the third detector, 3d, and thefourth detector, 4d, of the second set of detectors 1520, a third set ofdetectors 1530, and a fourth set of detector 1540, respectively, eachhave radially inward and radially outward positioned detection zones,relative to the second source 402, third source 403, and fourth source404, respectively, which are optionally dynamically selected as adetected thickness of the dermis 346 changes and/or as a state of thesample changes. As a result of a crossing geometry of the assortedsource-to-detector positions, such as illustrated, when a given selectedsource-to-detector distance is altered, such as to a radially inwardlypositioned detection zone, to maintain a constant mean sampling depth,the sample path still crosses the common sample zone. Thus, a commondepth and common sampling system is described, where the common samplezone comprises a cross-section length of less than 0.25, 0.5, 0.75, 1,1.5, 2, 3, or 4 mm.

Acousto-Optic Analyzer vs. (1) UPI and (2) an AOTF

An applied force-optic analyzer is described herein. Optionally andpreferably, the applied force results in a mechanical disturbance of thetissue resulting in a force being applied to the sample. However, in asub-case of the applied force-optic analyzer, the applied forcecomprises an acoustic force yielding an acousto-optic analyzer. Notably,in the sub-case of the applied force-optic analyzer being anacousto-optic analyzer, as used herein an acousto-optic analyzer starklycontrasts with both: (1) an ultrasonic photoacoustic imaging (UPI)system and (2) an acousto-optic tunable filter (AOTF) spectrometer, asdescribed infra.

Acousto-Optic Analyzer

As described, an acousto-optic analyzer (AOA) introduces an acousticvibration wave to the sample to impact the state of the sample, such astissue, and the state of the sample is measured using an optical probe.

Photoacoustic Imaging

In stark contrast, according to Wikipedia, ultrasonic photoacousticimaging, also referred to as (UPI), photoacoustic imaging (P1), and/oroptoacoustic imaging, delivers non-ionizing laser pulses to biologicaltissue, which results in absorbed energy and resultant heat in the formof transient thermoelastic expansions detected as wideband megaHertzultrasonic emissions detected by ultrasonic transducers. The detectedsignals are used to produce images. As optical absorbance relationshipsexist with physiological properties, such as hemoglobin concentrationand oxygen saturation, the detected pressure waves may be used todetermine hemoglobin and oxygen concentration.

Hence, an acousto-optic analyzer starkly contrasts with photoacousticimaging. Stated again, while the acousto-optic analyzer described hereinmay induce a heat wave like in photoacoustic imaging, in photoacousticimaging the sound wave is detected whereas photons, from an externalsource, are detected in the acousto-optic analyzer described aredetected after interacting with the sample beingdisplaced/heated/disturbed by the sound wave.

Acousto-Optic Tunable Filter

According to Wikipedia, an acousto-optic tunable filter (AOTF),diffracts light based on an acoustic frequency. By tuning the frequencyof the acoustic wave, the desired wavelength of the optical wave can bediffracted acousto-optically.

Hence, an acousto-optic analyzer (AOA) starkly contrasts with anacousto-optic tunable filter (AOTF) as, while the input sound wave ofthe AOA may diffract light, the separation of the input light is not theprimary use of the sound wave. Indeed, a narrow-band light emittingdiode (LED) is optionally used in conjunction with a broadband detectorin the acousto-optic analyzer making any separation of the narrow bandlight source pointless. Further, in the AOA, the sound wave is used tochange the state of the biological sample itself, whereas in the AOTFthe sound wave is introduced to a birefringent crystal in a wavelengthseparation module of the spectrometer and is not introduced into thesample.

Still yet another embodiment includes any combination and/or permutationof any of the elements described herein.

The main controller, a localized communication apparatus, and/or asystem for communication of information optionally comprises one or moresubsystems stored on a client. The client is a computing platformconfigured to act as a client device or other computing device, such asa computer, personal computer, a digital media device, and/or a personaldigital assistant. The client comprises a processor that is optionallycoupled to one or more internal or external input device, such as amouse, a keyboard, a display device, a voice recognition system, amotion recognition system, or the like. The processor is alsocommunicatively coupled to an output device, such as a display screen ordata link to display or send data and/or processed information,respectively. In one embodiment, the communication apparatus is theprocessor. In another embodiment, the communication apparatus is a setof instructions stored in memory that is carried out by the processor.

The client includes a computer-readable storage medium, such as memory.The memory includes, but is not limited to, an electronic, optical,magnetic, or another storage or transmission data storage medium capableof coupling to a processor, such as a processor in communication with atouch-sensitive input device linked to computer-readable instructions.Other examples of suitable media include, for example, a flash drive, aCD-ROM, read only memory (ROM), random access memory (RAM), anapplication-specific integrated circuit (ASIC), a DVD, magnetic disk, anoptical disk, and/or a memory chip. The processor executes a set ofcomputer-executable program code instructions stored in the memory. Theinstructions may comprise code from any computer-programming language,including, for example, C originally of Bell Laboratories, C++, C#,Visual Basic® (Microsoft, Redmond, Wash.), Matlab® (MathWorks, Natick,Mass.), Java® (Oracle Corporation, Redwood City, Calif.), andJavaScript® (Oracle Corporation, Redwood City, Calif.).

Herein, any number, such as 1, 2, 3, 4, 5, is optionally more than thenumber, less than the number, or within 1, 2, 5, 10, 20, or 50 percentof the number.

Herein, an element and/or object is optionally manually and/ormechanically moved, such as along a guiding element, with a motor,and/or under control of the main controller.

The particular implementations shown and described are illustrative ofthe invention and its best mode and are not intended to otherwise limitthe scope of the present invention in any way. Indeed, for the sake ofbrevity, conventional manufacturing, connection, preparation, and otherfunctional aspects of the system may not be described in detail.Furthermore, the connecting lines shown in the various figures areintended to represent exemplary functional relationships and/or physicalcouplings between the various elements. Many alternative or additionalfunctional relationships or physical connections may be present in apractical system.

In the foregoing description, the invention has been described withreference to specific exemplary embodiments; however, it will beappreciated that various modifications and changes may be made withoutdeparting from the scope of the present invention as set forth herein.The description and figures are to be regarded in an illustrativemanner, rather than a restrictive one and all such modifications areintended to be included within the scope of the present invention.Accordingly, the scope of the invention should be determined by thegeneric embodiments described herein and their legal equivalents ratherthan by merely the specific examples described above. For example, thesteps recited in any method or process embodiment may be executed in anyorder and are not limited to the explicit order presented in thespecific examples. Additionally, the components and/or elements recitedin any apparatus embodiment may be assembled or otherwise operationallyconfigured in a variety of permutations to produce substantially thesame result as the present invention and are accordingly not limited tothe specific configuration recited in the specific examples.

Benefits, other advantages and solutions to problems have been describedabove with regard to particular embodiments; however, any benefit,advantage, solution to problems or any element that may cause anyparticular benefit, advantage or solution to occur or to become morepronounced are not to be construed as critical, required or essentialfeatures or components.

As used herein, the terms “comprises”, “comprising”, or any variationthereof, are intended to reference a non-exclusive inclusion, such thata process, method, article, composition or apparatus that comprises alist of elements does not include only those elements recited, but mayalso include other elements not expressly listed or inherent to suchprocess, method, article, composition or apparatus. Other combinationsand/or modifications of the above-described structures, arrangements,applications, proportions, elements, materials or components used in thepractice of the present invention, in addition to those not specificallyrecited, may be varied or otherwise particularly adapted to specificenvironments, manufacturing specifications, design parameters or otheroperating requirements without departing from the general principles ofthe same.

Although the invention has been described herein with reference tocertain preferred embodiments, one skilled in the art will readilyappreciate that other applications may be substituted for those setforth herein without departing from the spirit and scope of the presentinvention. Accordingly, the invention should only be limited by theClaims included below.

1. An apparatus for sampling skin of a person as a part of noninvasiveanalyte property determination, comprising: an analyzer, comprising: aset of photonic sources and a set of detectors at least partiallyembedded in a probe housing, said probe housing comprising a sample sidesurface, said sample side surface comprising a sample zone; said samplezone separated from and between: (1) a first illumination zone opticallycoupled to a first source of said set of photonic sources and (2) afirst detection zone optically coupled to a first detector of said setof detectors; said sample zone separated from and between: (1) a secondillumination zone optically coupled to a second source of said set ofphotonic sources and (2) a second detection zone optically coupled to asecond detector of said set of detectors, said first illumination, saidsecond illumination zone, said first detection zone, said seconddetection zone, and said sample zone on said sample side surface of saidprobe housing; said first illumination zone at a first distance from acenter of the sample zone, said second illumination zone at a seconddistance from the center of the sample zone, said second distance atleast ten percent greater than said first distance.
 2. The apparatus ofclaim 1, said sample zone comprising a first cross-section distance ofless than two millimeters.
 3. The apparatus of claim 1, said sample zonecomprising a second cross-section distance of less than one millimeter.4. The apparatus of claim 2, said first detection zone comprising athird distance from said center of the sample zone, the third distancewithin ten percent of the first distance.
 5. The apparatus of claim 4,said first detection zone comprising a fourth distance from said centerof the sample zone, the fourth distance within ten percent of the seconddistance.
 6. The apparatus of claim 1, said set of detectors comprising:a third detector optically coupled to a third detection zone; and afourth detector optically coupled to a fourth detection zone, said firstdetection zone, said third detection zone, and said fourth detectionzone intersecting a line.
 7. The apparatus of claim 6, said line passingthrough said sample zone and said first illumination zone.
 8. Theapparatus of claim 1, said set of detectors comprising: a third detectoroptically coupled to a third detection zone; and a fourth detectoroptically coupled to a fourth detection zone, said first detection zone,said third detection zone, and said fourth detection zone intersectingan arc, said arc not passing through said sample zone.
 9. The apparatusof claim 1, further comprising: a first line passing through said firstillumination zone, said sample zone, and said first detection zone; anda second line passing through said second illumination zone, said samplezone, and said second detection zone, said first line noncollinear withsaid second line.
 10. The apparatus of claim 1, further comprising: afirst line passing through said first illumination zone, said samplezone, and said first detection zone; and a second line passing throughsaid second illumination zone, said sample zone, and said seconddetection zone, said first line collinear with said second line.
 11. Theapparatus of claim 1, said first source comprising at least one of: afirst laser diode; a first light emitting diode; and a broadband source.12. The apparatus of claim 11, said second source comprising at leastone of: a second laser diode; and a second light emitting diode.
 13. Theapparatus of claim 1, said first source configured to emit light over afirst wavelength range comprising a first mean wavelength, said secondsource configured to emit light over a second wavelength rangecomprising a second mean wavelength, said first mean wavelengthdiffering from said second mean wavelength by at least twentynanometers.
 14. The apparatus of claim 1, said analyzer furthercomprising: an off-center mass configured to shake at least a portion ofsaid analyzer at a rotation frequency.
 15. The apparatus of claim 1,said analyzer further comprising: a force system at least partiallyembedded in said analyzer, said force system configured to vibrate saidprobe housing.
 16. The apparatus of claim 1, said analyzer furthercomprising: a processor, said processor communicatively linked to aforce delivery system, said force delivery system configured tomechanically move, under control of said processor, at least one elementof said force delivery system relative to a position of said samplezone.
 17. The apparatus of claim 1, said analyzer further comprising: aband configured to secure said probe housing to an upper arm of theperson.
 18. The apparatus of claim 1, said set of source systemsconfigured to emit light in both: a 1500 to 1550 nm range and a 1600 to1800 nm range.
 19. The apparatus of claim 1, said first distance lessthan 1.5 millimeters and said second distance greater than 1.6millimeters.
 20. The apparatus of claim 1, said first distance less than1.0 millimeters and said second distance greater than 1.8 millimeters.